An ethnopharmacological review of Hyptis suaveolens (L.) Poit

This review aimed to provide a comprehensive overview of ethnobotanical uses, chemical constituents, posology, and toxicology of Hyptis suaveolens, and to address the significant medicinal benefits in order to promote its application. An extensive and systematic review of the literature was undertaken and all relevant abstracts and full-text articles analyzed and included in the review. A wide range of traditional uses are cited in the literature, ranging from uses for malaria, constipation, stomach problems, renal inflammation to external uses in repelling insects and treating injuries such as lacerations and burnrelated damage to skin and tissues. To date, pharmacological studies have demonstrated the significant activities of this plant that support uses such as antimicrobial, antidiabetic, antiulcer, and antiinflammatory. Numerous important phytochemicals, including 6 triterpenes, 8 diterpenes and 1 flavonoid have been isolated, identified and reported. The extracts and phytochemicals isolated from the plants show considerable potential for medicinal exploitation and utilization, including antimitotic, antiproliferative, cytotoxic, antioxidant, anti-inflammatory, antibacterial, antifungal, antiviral, anti-secretory, hepatoprotective, insecticidal, and acaricidal activities. As a medicinal plant, H. suaveolens is endowed with immense exploitation and utilization value and is widely used worldwide Therefore, further studies to fully elucidate its medicinal potential are warranted.


INTRODUCTION
Species of the family Lamiaceae, which are largely herbaceous and of economic importance, are found mostly in tropical, subtropical, and temperate parts of the world. Hyptis suaveolens (L.) Poit is belonging to the genus Hyptis and family Lamiaceae that includes 775 species worldwide, which are primarily found in South America. Plants of the Hyptis genus have been highlighted for numerous medicinal properties such as tumorigenic, antifertility, antimicrobial, mycotoxic, and phytotoxic activities [1]. Among these plants, Hyptis suaveolens (L.) Poit is an important traditional medicinal plant that was originally native to tropical America and is currently considered as a weed worldwide.
H. suaveolens (Fig. 1) is a fast-growing perennial and aromatic herb that is 0.4-2 m high with a quadrate stem that bears hair. The leaves are either ovate or obovate, generally measuring 3-5 cm long and 2-4 cm wide with serrulate margins and a long stalk while its petioles are up to 3 cm long. The plant starts flowering early at an age of 2-3 months and produces copious blue flowers in small cymes along branches that end with reduced leaves. The flowers are pollinated by numerous pollinators leading to enormous seed production [2][3].
H. suaveolens is commonly distributed in dense clumps along roadsides, in over-grazed pastures, and around stockyards throughout the tropics and subtropics, but is normally restricted to places where the soils have been profoundly disturbed. The plant is characterized by a strong minty smell when crushed. Most parts of this plant are used in medicine formulations for treating numerous ailments such as respiratory and gastrointestinal infections, indigestion, colic, stomachache, colds, fever, burns, wounds, cramps and various skin complaints and it is used as an antirheumatic and antisuporific bath [4][5][6].
H. suaveolens also has numerous synonyms, such as Gnoteris cordata Raf., Hyptis congesta Leonard., Hyptis graveolens Schrank, Marrubium indicum Blanco, Schaueria graveolens (Blume) Hassk. Or Schaueria suaveolens (L.) Hassk [12].Over the past years, few studies have focused on reviewing H. suaveolens in the literature and we did not find any comprehensive reviews of H. suaveolens, although its growing regions, phytochemistry, toxicity, and food and medicinal uses have been summarized to a certain extent [2,3,10,12]. To acquire provide additional knowledge on the considerable applicability and usefulness of this plant, here, we present a review of H. suaveolens that include its characteristics, uses, chemical constituents, posology, phytochemistry and toxicology to facilitate the development and utilization of H. suaveolens.  In confirming relevant entries, we considered publications up to the end of March 2020. Searches undertaken were found to be written in English, Portuguese, or Chinese.

Weed characteristics
H. suaveolens, considered to be a weed worldwide, is currently ranked according to the importance of its use in different areas (Table 4). For instance, it is considered a serious weed in Brazil, a principal weed in Peru and Tanzania, but is a common weed in Australia, India, Micronesia, Philippines, Taiwan, and Thailand. This species is found in Cambodia, Ceylon (Sri Lanka), Congo-Kinshasa, Colombia, Costa Rica, Benin, Fiji, Ghana, Indonesia, Jamaica, Lebanon, Malaysia, Mauritius, Melanesia, Mexico, Netherlands, New guinea, Nicaragua, Panama, South Africa, Senegal, the US, Venezuela, and Vietnam, where it is also considered a weed, but of unknown ranked status. In China, the species is known to exist among the flora of the country, but confirmatory evidence of its weed status is needed [13].

Distribution
H. suaveolens is found across more than 50 countries in over the seven continents (Figure 2) [2].

Traditional medicinal uses
The different traditional medicinal uses of various parts of H. suaveolens in over 23 countries are summarized in Table 1, Table 2 and Table 3, where they are arranged by frequency of the same use in different countries. Five of these countries are located in Central America, four in Asia (Bangladesh, China, India, and Thailand), four in Africa (Tanzania, Nigeria, Burkina Faso, and Kenya) two in the Caribbean (Jamaica and Curaçao), and one in South America (Brazil). A wide range of traditional medicinal uses of this plant are reported in the literature. These applications range from in vivo use for conditions affecting the respiratory system, gastrointestinal tract, and gynecological system to in vitro conditions affecting the skin [53]. This plant appears to be most commonly reported to be used in the treatment of fever and headache (reported in fourteen countries), as an insect repellent, for stomach disorders, skin conditions, injuries (five countries each), weakness (two countries), abnormal leucorrhea, renal disorders, dysentery, and malaria (three countries each). In addition, the plant is also less frequently reported to be used for male disorders and menorrhagia (two countries each).

Posology
For headaches and colds, a decoction is prepared from 6-12 g of H. suaveolens for oral administration with a decoction of the fresh plant used to wash the body. In Bangladesh, 2 g of the seeds of H. suaveolens are soaked in water with mishri (crystalline sugar) for a whole day and then consumed for treating underweight [26]. In Bidar District of Karnataka in India, a spoonful (10 g) of the seed extract is administered orally once a day for 3 days as a remedy for leucorrhoea and temporary male infertility. Documentation of traditional knowledge of medicinal plants used in Bidar District and Karnataka reports that in Seshachalam Biosphere Reserve Forest of Chittoor District and Andhra Pradesh India, 4-7 g of the leaf powder is rolled in beedi leaves, which is then smoked to relieve colds and nasal congestion [36]. With an iron-deficient diet and high incidences of bloodsucking helminths, people in Bastimentos and Panama struggle with iron deficiency anemia. Consequently, a black drink prepared from H. suaveolens is the ethnopharmacological treatment for these pathologies, including iron deficiency anemia that is widely used in Bastimentos and unique to this community [54].

Phytochemistry
Research on the phytochemistry of H. suaveolens are has revealed that extracts of its different plant contain alkaloids, flavonoids, terpenoids, and tannins [55,56]. The saponin content of the leaves and stems is 6.10% ± 0.42% and 10.50% ± 0.79 %, respectively, while saponins have not been found in the roots. The contents of alkaloids, flavonoids, and tannins in the leaves are 2.80 ± 0.28, 1.90 ± 0.14, and 5.50 ± 0.074 %, respectively. Compared to the stem, the contents of alkaloids, flavonoids, and tannins are 1.60 ± 0.00, 0.30 ± 0.14, and 0.23 ± 0.07 %.

Chemical constituents
Over the past years, the chemical constituents of H. suaveolens have been investigated widely in different the countries, and numerous new compounds have been isolated from this plant and their structures identified. In this paper, the dominant compounds isolated from different parts of H. suaveolens collected from various regions are summarized in Table 5 and Table 6. The structures of these compounds are mostly terpenoids including sesquiterpenes, diterpenes, triterpenes, and β-sitosterol. Most studies of the chemical constituents reported that they were mainly accumulated in the essential oil of the plant, but little attention has been focused on other extracts of H. suaveolens.

Toxicity
Extracts of H. suaveolens have shown effective insecticidal activity because of their toxicity to plant pests. The explanation for this biomechanism may be that the volatile oil of the extracts, which are characterized by a strong odor, can reduce the appetite of insects for the plants. The toxic effects of H. suaveolens are summarized in Table 7.    Leaf Infusion or crush and inhaled 52 a sherbet = Seeds are soaked in water in which mishri (crystalline sugar) has been dissolved and taken as a drink; b int = internal use; c ext = external use  β-caryophyllene, trans-α-bergamotene, caryophyllene oxide, 6-hydroxycarvotanacetone, bicyclogermacrene, (Z)-trans-α-bergamotol, terpinen-4-ol.

Essential oil Benin 73
Eucaliptoll, gama-ellemene, beta-pynene, (+)-3-carene, trans-beta-cariophyllene, germacrene Essential oil Brazil 74  suaveolens, most studies were conducted on its essential oils. Therefore, more new compounds from other parts of this plant still need to be isolated and identified because the specific constituents mediating the pharmacological activities have not been identified. Safety assessments of H. suaveolens suggest that it has acute or chronic toxicity against grain pests, which suggests that it could be used as a herbal insecticide or pesticide. In addition, to further explore and exploit the therapeutic potential of H suaveolens, quality control protocols are urgently needed to standardize this plant.

Acknowledgement
The authors are very thankful for Guangdong Pharmaceutical University for providing the necessary facilities and encouragement to carry out this work successfully.

Conflict of interest
No conflict of interest is associated with this work.

Contribution of authors
We declare that this work was done by the authors named in this article and all liabilities pertaining to claims relating to the content of this article will be borne by the authors.

Open Access
This is an Open Access article that uses a funding model which does not charge readers or their institutions for access and distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/ 4.0) and the Budapest Open Access Initiative (http://www.budapestopenaccessinitiative.org/rea d), which permit unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.